Process for the preparation of clausenamide

ABSTRACT

A new synthetic route to clausenamide having the formula ##STR1## has been found. It has been found that a compound of the formula ##STR2## can be oxidized to provide the stereochemically correctly configured product, clausenamide. A number of new compounds useful in the total synthesis of clausenamide have also been found. These compounds have the general formula ##STR3## wherein R is ##STR4## and CH 2  OH.

This is a division of application Ser. No. 915,309, filed Oct. 3, 1986,now allowed.

The invention relates to a process for the preparation of(±)3(S*),4(R*),5(R*),7(S*)-3-hydroxy-5-α-hydroxybenzyl-1-methyl-4-phenyl-pyrrolidin-2-one(clausenamide).

It is known that Rutaceae Clausena anicata is used as a folk medicine incertain parts of Africa [J. Mester et al., Planta Medica 32, 81 (1977)].It is also known that the crude extract of Clausena indica Oliv. hascardiovascular activity, and that two coumarin derivatives, clausmarin Aand B, isolated from Clausena pentaphalla (Roxb.) by thin layerchromatography have spasmolytic activity [Dhan Prakash et al., J. Chem.Soc. Chem. Commun. 1978, 281]. In addition, the aqueous extract ofleaves of Clausena Lansium (lour) Skeels is also regarded as aneffective agent for protecting the liver in Chinese folk medicine and isemployed against acute and chronic viral hepatitis. It has been possibleto isolate(±)3(S*),4(R*),5(R*),7(S*)-3-hydroxy-5-α-hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-one(clausenamide) of the formula (I) from this extract as one of the mainconstituents. ##STR5##

Clausenamide shows an antiamnesic action and an action affordingprotection from cerebral hypoxia in animal experiments. Since largeramounts are required for further pharmacological studies and, on theother hand, only 1.5 g of clausenamide are obtained from 4 kg of driedleaves by the expensive extraction process, it was necessary to providea process for the chemical synthesis of clausenamide.

The present invention relates to a process for the preparation of(±)3(S*),4(R*),5(R*),7(S*)-3-hydroxy-5-α-hydroxybenzyl-1-methyl-4-phenyl-pyrrolidin-2-one (I), characterised in that(±)4(R*),5(R*),7(S*)-5-hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-oneof the formula (II) ##STR6## is oxidised in inert organic solvents inthe presence of a base, if appropriate in the presence of an auxiliary.

It is to be described as decidedly surprising that exclusively thecorrectly configurated C₃ -C₄ -transhydroxylation product (I) is formedin a good yield with the aid of the process according to the invention.The product is identical to the clausenamide obtained from a plantextract. In comparison with the extraction process, larger amounts canbe provided in a shorter time and with less expenditure by the newprocess. In addition, the contamination of the clausenamide by otherplant active compounds which can be removed only with difficulty isexcluded.

The course of the reaction can be represented by the following equation:##STR7##

Oxidising agents which can be employed are organic or inorganic peroxocompounds, such as, for example, peroxoacetic acid, chloroperbenzoicacid or the molybdenum peroxide/pyridine complex, and in additionoxygen, ozone or oxygen transfer agents, such as, for example,2-sulphonyloxaziridine.

Possible solvents are the customary inert organic solvents which do notchange under the reaction conditions. These include, preferably,hydrocarbons, such as, for example, benzene, toluene, xylene, hexane,cyclohexane or petroleum fractions, ethers, such as diethyl ether,tetrahydrofuran or dioxane, alcohols, such as, for example, methanol,ethanol or propanol, halogenohydrocarbons, such as, for example,methylene chloride, chloroform, carbon tetrachloride or1,2-dichloroethane, glacial acetic acid, acetonitrile orhexamethylphosphoric acid triamide. It is also possible to use mixturesof the solvents mentioned.

The customary bases for enolate formation can be used as the bases.These include, preferably, alkali metal alcoholates, alkali metalamides, alkali metal hydrides or organo-alkali metal compounds, such as,for example, sodium or potassium methanolate, sodium or potassiumethanolate, potassium tert.-butanolate, sodium hydride, sodium amide,lithium diisopropylamide, butyl-lithium or phenyl-lithium; tertiaryamines, such as, for example, 1,5-diazabicyclo(4,3,0)non-5-ene or1,8-diazabicyclo(5,4,0)undec-7-ene, can likewise be employed.Particularly preferred bases are lithium diisopropylamide, lithiumhexamethylpiperidide and n-, sec.- or tert.-butyl- or phenyl-lithium.

The choice of base, solvent and, if appropriate, auxiliary depends onthe oxidation method selected.

The auxiliaries used are, if appropriate, substances which are capableof reducing the hydroperoxide intermediate stages formed in situ, inparticular when molybdenum peroxide pyridine or oxygen is used as theoxidising agent. Phosphites are preferably used for this, in particulartrialkyl or triaryl phosphites, such as, for example, trimethylphosphite, triethyl phosphite, tripropyl phosphite, triisopropylphosphite, tributyl phosphite or triphenyl phosphite.

Oxidation with molybdenum peroxide/pyridine in hexamethylphosphoric acidtriamide and with oxygen, in each case using phosphites, is particularlysuitable. Especially good yields are obtained in oxidation with oxygenin a solvent, such as tetrahydrofuran or hexamethylphosphoric acidtriamide, or if appropriate mixtures thereof, using triethyl phosphite.It has proved advantageous here to use lithium diisopropylamide orbutyl-lithium as the base.

The reaction temperatures can be varied between -100° C. and +20° C. Thereaction is preferably carried out between -78° C. and 0° C.

The hydroxylation by the process according to the invention can becarried out under normal pressure or under increased or reducedpressure. In general, it is carried out under normal pressure.

In carrying out the process according to the invention, 1 to 5,preferably 1 to 2.5, moles of base and 0.5 to 5, preferably 0.5 to 2,moles of the auxiliary are employed per mole of the starting compound.

The enolate of II is usually first prepared in the most suitable solventwith the aid of the base, and absolute oxygen is passed through thesolution, with the addition of phosphite, until no further change is tobe observed by thin layer chromatography. Working up of the reactionmixture is carried out in the customary manner known to the expert.

The starting compound of the formula (II) is new. It can be prepared bya process in which(±)(4R*),5(R*)-5-formyl-1-methyl-4-phenyl-pyrrolidin-2-one of theformula (III) ##STR8## is reacted with organometallic compounds, such asGrignard reagents or titanium- or lithium-organyls, in suitable solventsin a temperature range from -20° C. to +50° C., preferably from -10° C.to +30° C., and, if appropriate, the product is epimerised on carbonatom 7.

Particularly suitable organometallic compound here are phenyl-magnesiumbromide or chloride or phenyl-triisopropoxytitanium.

Suitable solvents are all the inert organic solvents which are usuallyemployed in reactions with Grigard reagents or other organometallicreagents. These include, preferably, ethers, such as diethyl ether ortetrahydrofuran, if appropriate mixed with hexane.

The reaction can be carried out by a process analogous to processeswhich are known from the literature, such as are described, for example,by D. Seebach, B. Weidmann and L. Widler in "Modern Synthetic Methods1983" page 217 et seq. (Verlag Salle und Sauerlander) or inHouben-Weyl's "Methoden der organischen Chemie" ("Methods of OrganicChemistry") Volume XIII/2a, page 289 et seq., page 302 et seq., or by N.L. Drake and G. B. Cooke in Organic Synthesis, Coll. Vol. II, 406 etseq. (1963).

Depending on the nature of the organometallic reagent used, the(±)4(R*),5(R*),7(R*)-5-α-hydroxybenzyl-1-methyl-4-phenyl-pyrrolidin-2-oneR*-configurated on carbon atom 7, of the formula (IIa) ##STR9## canfirst be formed, and is then epimerised by oxidation to(±)4(R*),5(R*)-5-benzoyl-1-methyl-4-phenylpyrrolidin-2-one (IV)##STR10## and subsequent reduction of IV to give the 7-S*-configuratedproduct (II).

The oxidation of IIa to IV is carried out by a process analogous toknown processes with dimethylsulphoxide as the oxidising agent, with theaddition of anhydrides, in particular trifluoroacetic anhydride, insuitable organic solvents, in particular in halogenohydrocarbons, suchas, for example, methylene chloride or chloroform, or hydrocarbons, suchas benzene, toluene, xylene or hexane, or ethers, such as diethyl ether,dioxane or tetrahydrofuran, or a mixtures of the solvents mentioned,such as is described, for example, by S. L. Huang, K. Omura and D. Swernin Synthesis 1980, 297.

The reduction of IV to II can be carried out with the customary reducingagents. Metal hydrides and complex metal hydrides, such as, for example,lithium boranate, lithium hydridoborates, sodium hydridoboranates,boranes, sodium hydridoaluminates, lithium hydridoaluminates or tinhydrides, are particularly suitable for this. Lithium hydridoborates,such as, for example, lithium hydrido-triethyl-borate or lithiumhydrido-tris(1-methylpropyl)borate, or sodium borhydride areparticularly preferably employed.

Suitable solvents are the customary inert organic solvents used inreductions with hydrides. These are preferably ethers, such as diethylether and tetrahydrofuran. The reduction is carried out by a methodanalogous to known methods [W. Friedrichsen in Houben-Weyl, "Methodender organischen Chemie" ("Methods of Organic Chemistry") VIII/1b, 145 etseq; and H. C. Brown, S. Krishnamurthy, Chem. Commun. 1972, 868].

The compound (IIa) can also be epimerised by a process analogous toother known processes, such as are described, for example, by O.Mitsunobu in Synthesis 1981, 1.

The preparation of II can be illustrated by the following equation:##STR11##

If the readily accessible phenyl-magnesium bromide is used as theorganometallic reagent, almost exclusively the "incorrectly"configurated IIa is formed, and is epimerised to the "correctly"configurated II in the manner described.

The present invention also relates to the new compounds of the formulaeIIa, IV and III.

The aldehyde of the formula III can be prepared in accordance with thefollowing equation: ##STR12##

According to this equation,5,5-diethoxycarbonyl-4-phenylpyrrolidin-2-one (V) is methylated in stepa with a methylating agent, such as, for example, methyl bromide, methyliodide, methyl p-toluenesulphonate, diazomethane or dimethyl sulphate,if appropriate in the presence of a base, such as sodium, sodiumhydride, sodium amide, butyl-lithium or lithium diisopropylamide, insuitable solvents, such as diethyl ether, tetrahydrofuran,dimethylformamide or hexamethylphosphoric acid triamide, at temperaturesfrom -20° to +80° C., preferably from 0° C. to +40° C. Methylation withmethyl iodide in dimethylformamide is especially suitable. It has provedadvantageous here to use sodium hydride as the base. The reaction iscarried out and the product is worked up by customary methods familiarto the expert.

In step b, 5,5-diethoxycarbonyl-1-methyl-4-phenylpyrrolidin-2-one (VI)is hydrolyzed and decarboxylated by a process analogous to thatdescribed by P. Pachaly in Chem. Ber. 104, (2), 412-39 (1971), a mixtureof the isomers VIIa and VIIb being obtained. After separation of thecis/trans isomers VIIa and b by recrystallization or chromatography,VIIa is reduced to(±)4(R*),5(R*)-5-hydroxymethyl-1-methyl-4-phenylpyrrolidin-2-one (VIII)(step c).

The reduction of VIIa to VIII is carried out by the same method andunder the same conditions as have already been described for thereduction of IV to II.

The oxidation of VIII to III (step d) is carried out by the same methodand under the same conditions as have already been described for theoxidation of IIa to IV.

The starting compound V is known from the literature [G. H. Cocolas, W.H. Hartung, J. Am. Chem. Soc. 79, 5203 (1957); and F. Zymalkowski, P.Pachaly, Chem. Ber. 100, 1137 (1967)].

The overall synthesis of clausenamide with all the new intermediateproducts is illustrated in the following equation: ##STR13##

PREPARATION EXAMPLES Example 1 (±)5,5-Diethoxycarbonyl-4-phenylpyrrolidin-2-one ##STR14##

A solution of 18 g (0.8 gram atoms) of sodium in 400 ml of absoluteethanol was added dropwise to a suspension of 432 g (2 moles) of diethylacetamidomalonate in 1.6 l of absolute ethanol at room temperature underan N₂ atmosphere. 564 g (3.2 moles) of ethyl cinnamate were slowly addedand the mixture was then heated at the boiling point for 24 hours.

For working up, the mixture was allowed to come to room temperature, 2.5l of chloroform were added and the mixture was neutralized with aceticacid. It was washed thoroughly with water (5×in each case 500 ml), driedover MgSO₄ and concentrated on a rotary evaporator. The oily residue wasdissolved in a little acetone, hexane was added until crystallizationoccurred, and further hexane was then added until no further cloudinesswas to be observed at the dropwise addition point. Filtration withsuction gave 398 g (54%) of the title compound of melting point 97°-99°C. Chromatography of the mother liquor (toluene/ethyl acetate) gave afurther 85 g (14%) of the title compound, total yield 413 g (68%).

IR(KBr): ν=1770 (ester), 1700 (amide)

¹ H-NMR (300 MHz, CDCl₃): δ=0.84 and 1.28 (in each case t, J=7.5 Hz; 6H,CH₂ CH₃); ABX signal: δ_(A) =2.63, δ_(B) =2.96 (J_(AB) =17.3 Hz, J_(AX)=6 Hz, J_(BX) =9 Hz; 2H, C(3)-H); 3.66 and 3.71 (in each case m, 2H,cis-CH₂ CH₃); 4.28 (m, 2H, trans-CH₂ CH₃); 4.39 (dd, J_(AX) =6 Hz,J_(BX) =9 Hz, 1H, C(4)-H); 6.95 (br, 1H, NH); and 7.47 (br, 5H, C₆ H₅).

EXAMPLE 2 (±) 5,5-Diethoxycarbonyl-1-methyl-4-phenyl-pyrrolidin-2-one##STR15##

A solution of 100 g (0.33 mole) of (±)5,5-diethoxycarbonyl-4-phenylpyrrolidin-2-one in 500 ml of absolutedimethylformamide was added dropwise to a suspension of 9.64 g (0.36mole) of sodium hydride in 200 ml of absolute dimethylformamide at roomtemperature under an N₂ atmosphere. The mixture was subsequently stirredat room temperature until the evolution of gas had ended, a solution of93.7 g (0.66 mole) of methyl iodide in 50 ml of absolutedimethylformamide was then added and the mixture was stirred at roomtemperature until all the starting material had reacted (about 1 hour,thin layer chromatography check). The reaction mixture was poured into 2l of buffer solution, pH=7, and extracted five times with 600 ml ofdiethyl ether each time. Drying of the organic extracts (MgSO₄) andstripping off of the solvent in vacuo gave 105 g (99.6%) of the titlecompound (95% pure according to the ¹ H-NMR spectrum), which was furtherreacted directly. A sample was distilled in a bulb tube (boilingpoint₀.5 : 240° C.) for analysis, R_(f) : 0.36 (toluene/ethyl acetate:2/1),

IR (film): ν=1735 (ester), 1700 (amide)

¹ H-NMR (500 MHz, CDCl₃): δ=0.9 and 1.33 (in each case t, J=7.5 Hz; 6H,CH₂ CH₃); ABX signal: δ_(A) =2.66, δ_(B) =3.0 (J_(AB) =18 Hz, J_(AB) =6Hz, J_(BX) =8.3 Hz; 2H, C(3)-H); 3.06 (s; 3H, N-CH₃); 3.62 and 3.79 (ineach case m, 2H, cis-CH₂ CH₃); 4.31 (m, 3H, trans-CH₂ CH₃) and C(4)-H);and 7.26 (m, 5H, C₆ H₅).

EXAMPLE 3 (±)4(R*),5(R*) [I] and ±4(R*),5(S*)-5-ethoxycarbonyl-1-methyl4-phenylpyrrolidin-2-one [II] ##STR16##

49.5 g (0.156 mole) of barium hydroxide octahydrate are heated in 483 mlof distilled water at 70° C. until an almost clear solution is formed. Asolution of 100 g (0.313 mole) of(±)5,5-diethoxycarbonyl-1-methyl-4-phenylpyrrolidin-2-one in 724 ml ofethanol was added (clear solution) and the mixture was subsequentlystirred at 70° C. for 20 minutes until the starting material had reactedcompletely (about 20 minutes, thin layer chromatography check). Themixture was cooled and acidified to pH=1-2, while cooling with ice, andthe ethanol was stripped off in vacuo (bath temperature 30°-40° C.). Thesolid was filtered off with suction and aqueous phase was extracted,with addition of sodium chloride, 3 times with 200 ml of ethyl acetateeach time. Drying and stripping off of the solvent gave a residue whichwas combined with the solid obtained above, and the mixture was dried ina desiccator over P₄ O₁₀ under a high vacuum for 24 hours. The solid wasthen heated to 170° C. in an oil bath, while stirring thoroughly, untilthe evolution of gas had ended (5-10 minutes). Cooling and flashchromatography (cyclohexane/ethyl acetate=1/1, finally with ethylacetate) gave 39.3 g (50.7%) of [I] with R_(f) =0.10 and 19.6 g (25.3%)of [II] with R_(f) =0.20 (in each case in cyclohexane/ethyl acetate1/1).

IR(KBr): δ=1736, 1690 cm⁻¹

¹ H-NMR (200 MHz, CDCl₃): [I] δ=0.83 (t, J=7.5 Hz; 3H, CH₂ CH₃) ABXsignal: δ_(A) =2.67, δ_(B) 2.95 (J_(AB) =17.5 Hz, J_(AX) =9 Hz, J_(BX)=10 Hz, 2H, C(3)-H), 2.87 (s, 3H, N-CH₃), 3.75 (m, 2H, CH₂ CH₃); 3.91(q, J=9-10 Hz, 1H, C(4)-H), 4.36 (d, J=9 Hz, 1H, C(5)-H), 7.28 (m, 5H,C₆ H₅).

[II] δ=1.30 (t, J=7.5 Hz, 3H, CH₂ CH₃); ABX signal: δ_(A) =2.54, δ_(B)=2.82 (J_(AB) =18.5 Hz, J_(AX) =5 Hz, J_(BX) =9 Hz, 2H, C(3)-H), 3.80(s, 3H, N-CH₃), 3.53 (ddd, J=9 Hz, J=5 Hz, J=4 Hz, 1H, C(4)-H), 4.07 (d,J=4 Hz, 1H, C(5)-H), 4.27 (m, 2H, CH₂ --CH₃) 7.3 (m, 5H, C₆ H₅).

Example 4(±)4(R*),5(R*)-5-Hydroxymethyl-1-methyl-4-phenylpyrrolidin-2-one##STR17##

0.317 mole of LiB(Et)₃ H (as in 1M solution in tetrahydrofuran, 316.9ml) was added dropwise to a solution of 39.2 g (0.159 mole) ofcis-4(R*),5(R*)-5-ethoxycarbonyl-1-methyl-4-phenylpyrrolidin-2-one in390 ml of absolute tetrahydrofuran at -15° to 20° C. under an N₂atmosphere.

The reaction mixture was subsequently stirred at 0° C. for 1 hour,poured into about 200 ml of ice-cold 2N hydrochloric acid and extractedtwice with 200 ml of ethyl acetate each time. The aqueous phase wassaturated with sodium chloride and extracted twice more with 200 ml ofethyl acetate each time. The collected organic extracts were washed witha little water, dried over MgSO₄ and concentrated on a rotaryevaporator. The residue was made to crystallize with a little ether andthe product was then precipitated with pentane until no furthercloudiness was to be observed at the dropwise addition point. Afterfiltration with suction and drying, 29.1 g (89.2%) of the title compoundof melting point 93°-95° C. were obtained.

IR(KBr): ν=3324, 1687 cm⁻¹

¹ H-NMR (300 MHz, CDCl₃): δ=AB-part of ABM system, δ_(A) =2.59, δ_(B)=2.97 (in each case dd, J_(AB) =15 Hz, J_(AM) =7.5 Hz, J_(BM=) 9 Hz, 2H,C(3)-H); 2.97 (s, 3H, N--CH₃) AB-part of ABM system, δ_(A) =3.36, δ_(B)=3.62 (in each case dd, J_(AB) =11.2 Hz, J_(AM) =J_(BM) =3 Hz, 2H,C(7)-H; 3.72-3.85 (m, 2H, C(4)-H, C(5)-H); 7.32 (m, 5H, C₆ H₅).

Example 5 4(R*),5(R*)-5-Formyl-1-methyl-4-phenylpyrrolidin-2-one##STR18##

A solution of 29.7 ml of trifluoroacetic anhydride in 56 ml of absolutemethylene chloride was added dropwise at -60° C. to a solution of 19.9ml (0.28 mole) of absolute dimethyl-sulphoxide in 140 ml of absolutemethylene chloride under an N₂ atmosphere in the course of 10 minutes.The mixture was stirred at this temperature for 15 minutes and asolution of 28.8 g (0.140 mole) of4(R*),5(R*)-5-hydroxymethyl-1-methyl-4-phenylpyrrolidin-2-one in 250 mlof methylene chloride was added dropwise such that the temperature didnot exceed -60° C. The mixture was subsequently stirred at -60° C. for90 minutes, warmed briefly to -30° C. (5-10 minutes) and cooled again to-60° C. 56 ml of absolute triethylamine were slowly added at thistemperature and the mixture was stirred at -60° C. for 30 minutes andwarmed to room temperature. 600 ml of water were added, the phases wereseparated and the aqueous phase was extracted three times with 250 ml ofmethylene chloride each time. The collected organic extracts were washedtwice with 300 ml of water each time, dried over magnesium sulphate andextracted. 28.3 g (100%) of the title compound with R_(f) =0.25 (ethylacetate) (91% pure according to the ¹ H-NMR spectrum) were obtained. Thecrude product thus obtained was further reacted directly, after drying(24 hours, high vacuum).

IR (CHCl₃): ν=1734, 1689 cm⁻¹

¹ H-NMR (300 MHz, CDCl₃): δ 2.79 (dd, J=5.3 Hz, J=9.7 Hz, 2H, C(3)-H);2.91 (s, 3H, N--CH₃); 4.02 (q, J=9.7 Hz, 1H, C(4)-H); 4.30 (dd, J=1 Hz,J=9.7 Hz, 1H, C(5)-H); 7.3 (m, 5H, C₆ H₅), 9.17 (d, J=1 Hz, 1H, CHO).

Example 64(R*),5(R*),7(R*)-5-α-Hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-one##STR19##

A solution of 24.8 g (16.7 ml, 0.156 mole) of bromobenzene in 44 ml ofabsolute tetrahydrofuran was added dropwise to 3.84 g of Mg filingsunder N₂ such that the tetrahydrofuran simmered. 100 ml of absolutetetrahydrofuran were then added and the mixture was heated at theboiling point under reflux until all the magnesium had dissolved (1-2hours).

The mixture was cooled to 0° C. and a solution of 24.7 g (0.12 mole) of4(R*),5(R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one in 250 ml ofabsolute tetrahydrofuran was added dropwise, with vigorous stirring,such that the temperature did not exceed 5° C. If necessary, absolutetetrahydrofuran had to be added for better stirrability. The reactionmixture was then stirred at 0°-5° C. for 1 hour, poured onto 350 ml of0.5N HCl-ice and extracted four times with 300 ml of ethyl acetate eachtime and twice with 300 ml of methylene chloride each time. Thecollected ethyl acetate and methylene chloride extracts were washed(separatelyl) twice with 200 ml of water each time, combined and driedover magnesium sulphate. The residue which remained after stripping offof the solvent (in vacuo) was triturated with 100 ml of ether untilcrystallization occurred. 500 ml of pentane were then slowly added andthe mixture was left to stand overnight in a refrigerator. Filtering offof the solid with suction gave 25 g (74.3%) of the title compound ofmelting point: 210°-212° C.

For analysis, the product was recrystallized from acetone (meltingpoint: 214°-5° C.).

IR(KBr) ν=3362 (br), 1654 cm⁻¹

¹ H-NMR (300 NHz, d₆ -DMSO): δ=2.21 (s, 3H, NCH₃); 2.24 (dd, A-part ofABM system, J_(AB) =15.7 Hz, J_(AM) =9.4 Hz, 1H, cis-C(3)-H); 3.05 (dd,B-part of ABM system, J_(BM) =12.7 Hz, 1H, trans-C(3)-H); 3.80 (dt,M-part of ABM system, J_(AM) =8.5 Hz, J_(AB) =12.7 Hz, J₄.5 =8.5 Hz, 1H,C(4)-H); 4.15 (dd, J=8.5 Hz, J=1 Hz, 1H, C(5)-H); 4.26 (dd, J=6 Hz, J=1Hz, 1H, C(7)-H); 5.35 (d, J=6 Hz, 1H, OH); 7.15-7.5 (m, 10H, C₆ H₅).

Example 7 4(R*),5(R*)-5-Benzoyl-1-methyl-4-phenylpyrrolidin-2-one##STR20##

A solution of 18 ml of trifluoroacetic anhydride in 34 ml of absolutemethylene chloride was added dropwise to a solution of 12.24 ml (0.171mole) of absolute dimethylsulphoxide in 87 ml of absolute methylenechloride at -60° C. under an N₂ atmosphere in the course of 10 minutes.The mixture was subsequently stirred at this temperature for 15 minutesand a solution of 24 g (0.085 mol) of4(R*),5(R*),7(R*)-5-α-hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-one inabout 700 ml of absolute methylene chloride was added dropwise such thatthe temperature did not exceed -60° C. The mixture was subsequentlystirred at -60° C. for 90 minutes, warmed briefly to -30° C. (9-10minutes) and cooled again to -60° C. 34.2 ml of triethylamine wereslowly added at this temperature and the mixture was stirred at -60° C.for 20 minutes and warmed to room temperature. 370 ml of water wereadded, the phases were separated and the aqueous phase was extractedthree times with 250 ml of methylene chloride each time. The combinedorganic extracts were washed twice with 300 ml of water each time, driedover magnesium sulphate and concentrated on a rotary evaporator. Theresidue was evaporated in a rotary evaporator twice with 200 ml of ethereach time. 23.5 g (100%) of the title compound were obtained as a solidof melting point: 115°-116° C. The crude product, which was pureaccording to the ¹ H-NMR spectrum, was further reacted directly.

For analysis, a sample was chromatographed over silica gel with ethylacetate (R_(f) =0.25), melting point: 121°-2° C.

IR(KBr): ν=1695, 1682 cm⁻¹

¹ H-NMR (300 MHz, CDCl₃) δ=2.78 and 2.91 (AB-part of ABM spectrum,J_(AB) =16.5 Hz, J_(AM) =J_(BM) =8.3 Hz, 2H, C(3)-H); 2.88 (s, 3H,N-CH₃); 4.02 (q, J=8.3 Hz, 1H, C(4)-H); 5.42 (d, J=8.3 Hz, 1H, C(5)-H);7.0, 7.21, 7.59 and 7.50 (in each case m, 10H, C₆ H₅).

Example 84(R*),5(R*),7(S*)-5-α-Hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-one##STR21##

83 mmol of LiB(Et)₃ H (83 ml of a 1M solution in tetrahydrofuran) wereadded dropwise to a solution of 23 g (82.3 mmol) of4(R*),5(R*)-5-benzoyl-1-methyl-4-phenylpyrrolidin-2-one in 200 to 270 mlof absolute tetrahydrofuran at -15° to -20° C. under an N₂ atmosphere.The reaction mixture was subsequently stirred at 0° C. for 1 hour,poured into 100 ml of ice-cold 1N HCl and extracted twice with 200 ml ofethyl acetate each time. The aqueous phase was saturated with sodiumchloride and extracted twice more with 200 ml of ethyl acetate eachtime. The combined organic extracts were dried over MgSO₄ andconcentrated on a rotary evaporator. The residue was dissolved inmethylene chloride and washed twice with 100 ml of water each time. Theorganic phase was dried (MgSO₄) and concentrated on a rotary evaporator.The residue was made to crystallize with 100 ml of ether, and pentanewas then slowly added, with stirring, until no further cloudiness was tobe observed at the dropwise addition point. The precipitate was filteredoff with suction and dried. 16.6 g (72%) of the title compound ofmelting point: 189°-195° C. were obtained.

The product is 95% pure according to ¹ H-NMR and was further reacteddirectly.

For analysis, the product was recrystallised from acetone (meltingpoint: 197°-8° C.).

IR(KBr): ν=3251, 1692 cm⁻¹

¹ H-NMR (300 MHz, DMSO): δ=1.97 and 2.05 (ABM signal, J_(AB) =13.5 Hz,J_(AM) =8.2 Hz, J_(BM) =13 Hz, 2H, C(3)-H); 2.91 (s, 3H, N-CH₃); 3.82(dt, J_(AM) =J₄.5 =8.2 Hz, J_(BM) =13 Hz, 1H, C(4)-H); 4.27 (dd, J=8.2Hz, J=1.5 Hz, 1H, C(5); 4.65 (dd, J=1.5 Hz, J=3.5 Hz, 1H, C(7)-H); 5.34(d, J=3.5 Hz, 1H, OH); 6.70, 7.11 and 7.25 (in each case m, 10H, C₆ H₅).

Example 93(S*),4(R*),5(R*),7(S*)-3-Hydroxy-5-α-hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-one(clausenamide) ##STR22##

A solution of 17.7 g (62.0 mmol) of4(R*),5(R*),7(S*)-5-α-hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-one in490 ml of absolute tetrahydrofuran and 130 ml of absolutehexamethylphosphoric acid triamide was introduced into a flask which hadbeen heated thoroughly in vacuo and flushed with pure nitrogen, and thesolution was cooled to -70° C. A solution of 0.152 mole of lithiumdiisopropylamide in 180 ml of absolute tetrahydrofuran/hexane (preparedfrom 22.1 ml of diisopropylamine in 80 ml of tetrahydrofuran by additionof 103 ml of a 1.5N solution of n-butyl-lithium in hexane at -20° C. to0° C.) was added dropwise at this temperature. The mixture wassubsequently stirred at -70° C. to -60° C. for 1 hour, 5.3 ml of freshlydistilled trimethyl phosphite (dissolved in a little absolutetetrahydrofuran) were added and absolute oxygen (dried over H₂ SO₄ andP₄ O₁₀) was passed in (50-100 ml/minute). As soon as theproduct/starting material ratio no longer changed (2-3 hours) accordingto thin layer chromatography check (SiO₂ ; ethyl acetate/MeOH: 2/1;R_(f) =0.3 for the title compound, R_(f) =0.37 for the startingcompound, staining with molybdatophosphoric acid spray reagent), themixture was poured onto 600 ml of 0.5N HCl, while cooling with ice, andif appropriate acidified to pH 3 to 4.

The phases were separated and the aqueous phase was extracted four timeswith 300 ml of ethyl acetate each time. The combined organic extractswere washed three times with 300 ml of water each time, dried over MgSO₄and concentrated on a rotary evaporator. The residue was taken up in50-100 ml of ether, the mixture was stirred until crystallizationstarted and pentane was slowly added, with stirring, until no furthercloudiness was to be observed at the dropwise addition point. Themixture was left to stand overnight in a refrigerator and filtered withsuction. about 17 g of a crude solid which, in addition to the titlecompound, contained about 35-40% of starting material were obtained. Forpurification, the product is recrystallized twice from methanol. Thetitle compound is then obtained in a purity of about 95%. Chromatographyover aluminum oxide (neutral) proceeds without losses and with recoveryof the pure starting material. For this, the crude product is absorbedonto silica gel (dissolving in MeOH under the influence of heat,addition of 5 parts by weight of silica gel, concentration on a rotaryevaporator and evaporation on a rotary evaporator several times withethyl acetate until an MeOH-free product as dry as dust results). Theadsorbate is introduced onto a column containing Al₂ O₃ (neutral, 50parts by weight) and the starting material is eluted first with ethylacetate (flash chromatography, check by thin layer chromatography andanalytical high performance liquid chromatography). The title compoundis then eluted with ethyl acetate/methanol mixtures (40/1, 20/1 and then10/1). 8.6 g (46.1%) of the title compound of melting point: 236°-7.5°C. (authentic clausenamide: 236°-7° C.) and a purity of about 98%(according to ¹ H-NMR, contains about 2% of starting material) wereobtained. It was possible to recover 5 g of the pure starting material.

IR(KBr): ν=3402, 3321, 1689 cm⁻¹

¹ H-NMR (300 MHz, DMSO): δ=3.01 (s, 3H, N-CH₃); 3.50 (dd, J=8 Hz, J=10.5Hz, 1M, C(4)-H); 3.82 (dd, J=10 Hz, J=7 Hz, 1H, C(3)-H); 4.30 (dd, J=8Hz, J=2 Hz, 1H, C(5)-H); 4.65 (dd, J=2 Hz, J=3 Hz, 1H, C(7)-H), 5.39 (d,J=7 Hz, 1H, C(3)-OH); 5.45 (d, J=3 Hz, 1H, C(7)-OH; 6.61-6.64 (m, 2H,aromatic H) and 7.03-7.28 (m, 8H, aromatic H).

What is claimed is: 1.(±)4(R*),5(R*),7(S*)-5-α-Hydroxybenzyl-1-methyl-4-phenylpyrrolidin-2-oneof the formula ##STR23## 2.(±)4(R*),5(R*)-5-Formyl-1-methyl-4-phenyl-pyrrolidine-2-one of theformula ##STR24## 3.(±)4(R*),5(R*)-5-Benzoyl-1-methyl-4-phenylpyrrolidin-2-one of theformula ##STR25## 4.(±)4(R*),5(R*)-5-Hydroxymethyl-1-methyl-4-phenylpyrrolidin-2-one of theformula ##STR26##